Project Summary. The cycloaddition between a small-ring donor-acceptor compound and a dipolarophile produces stereochemically rich heterocyclic and carbocyclic building blocks that are useful in the construction of bioactive small molecules. Improved access to these building blocks will facilitate the construction of a wide range of useful molecular scaffolds that could act as tool compounds to probe biological systems or as drug candidates to treat disease. Current methods for these cycloadditions employ either Lewis acid or transition metal catalysts to partially stabilize the zwitterionic transition state. This proposal aims to leverage a bifunctional catalyst system that will more effectively stabilize both charge components of the transition state, removing the requirement for strong anion and cation stabilizing groups on the substrate, thereby increasing the substrate scope of this transformation. Specifically, current methods stabilize only one of the two charged functional groups in the zwitterionic transition state of the donor-acceptor ring, relying on substrate functionality to stabilize the opposing charge. In contrast, employing a hydrogen-bond donor (HBD)/cation-? catalyst system will stabilize both charge components using optimized catalyst-substrate interactions. The anionic component will be stabilized through a hydrogen-bond interaction between an HBD donor on the catalyst and an enolate on the substrate, while the cationic component will be stabilized through a cation-? interaction between an aryl ring on the catalyst and the cation of the zwitterionic intermediate. The use of multiple noncovalent interactions with a chiral catalyst should produce a well-defined catalyst-substrate construct, allowing for effective differentiation of enantiotopic transition states leading to enantioenriched products. Successful realization of this strategy will broaden the substrate scope of these reactions, increasing the chemical space accessible using this type of chemistry. Ideally, this method will become a universal tool for diverse carbocyclic and heterocyclic frameworks, simplifying disconnections for biologically relevant molecules. A variety of useful heterocycles and carbocycles can be generated from simple starting materials with the proposed catalyst system, including furans, pyrans, substituted cyclopentane rings, and amino acid derivatives. Many of these products are common structural motifs found in bioactive natural products such as polyketides, terpenes, and nonribosomal peptides, and this method would facilitate access to these useful molecules.